Immunologic competence depends upon activation and differentiation of various types of lymphocytes. I plan to study the biochemical events associated with and the mechanisms controlling such activation and differentiation from three different points of view. These studies will be performed utilizing human peripheral blood lymphocytes obtained from normals as well as individuals with primary or secondary defects in cellular, humoral or both types of immunity when they become available. First I will study the role of cyclic and non-cyclic nucleotides and nucleosides and the enzymes of their metabolism in the events associated with mitogen-induced lymphocyte activation. Cells from patients with the recently discovered immunodeficiency due to a defect in one of these enzymes, adenosine deaminase, will be compared with normals to study the role of this enzyme. The possibility that the lack of adenosine deaminase in active form results in a toxic accumulation of adenosine and its derivatives including inhibitory levels of cAMP and ATP will be investigated by studying the effects of adenosine and inhibitors of adenosine deaminase. Second, I will search for the activation or repression of enzymes and their isozymes associated with lymphocyte stimulation by means of starch gel electrophoresis, in order to elucidate the metabolic and genetic control of stimulation and its disturbance in immune deficiency diseases. Third, I will study a variety of lysosomal proteases and other products contained and released by activated lymphocytes since these may play a role as mediators of cytotoxicity and in activation of other cells during the immune response.